10alpha-pregnan-19-ol derivatives



United States Patent 3,205,459 o4-PREGNAN-19-OL DERIVATIVES Alexander D.Cross, Mexico City, Mexico, assignor to Syntex Corporation, Panama,Panama, a corporation of Panama No Drawing. Filed Oct. 19, 1962, Ser.No. 231,831 19 Claims. (Cl. 260-23955) The present invention relates tonovel cyclopentanophenanthrene derivatives and to a process for theproduction thereof.

More particularly the present invention relates to novell0a-pregnan-19-ol derivatives.

The novel compounds of the present invention are represented by thefollowing formulae:

In the above formulae X represents hydrogen, fluorine, chlorine ormethyl all having on or ,8 configurations; R represents hydrogen, ahydroxyl group or a hydrocarbon carboxylic acyloxy group of less than 12carbon atoms; T represents hydrogen, a-hYdfOXY, oc-acyloxy, wmethyl orfi-methyl; T and R together represent the group being in the 16a,17a-positions, wherein R and- R each represents hydrogen or ahydrocarbon residue of up to 8 carbon atoms of straight, branched,cyclic or mixed aliphatic cyclic chain, or aromatic, such as methyl,ethyl, isopropyl, phenyl, methyl-cyclohexyl and the like; R representshydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbonatoms; and Z represents a double bond or a saturated linkage between C-1and C-2.

The acyl and acyloxy groups are derived from hydrocarbon carboxylicacids containing less than 12 carbon atoms which may be saturated orunsaturated, of straight, branched, cyclic or cyclic-aliphatic chain,aromatic and may be substituted by functional groups such as hydroxy,alkoxy containing up to 5 carbon atoms, acyloxy containing' up to 12carbon atoms, nitro, amino or halogen. Typical ester groups are theacetate, propionate, enanthat'e, benzoate, trimethylacetate,t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, and,B-chloropropionate.

The compounds represented by the above formulas are powerfulprogestational agents with good oral activity. In addition they haveanti-androgenic, anti-gonadotrophic and anti-estrogenic properties andare very useful in fertility control; Furthermore they may be used inthe treatment of premenstrual tension and exhibit blood cholesterolloweringand diuretic activities. When applied topically, these compoundsare very useful in the treatment of acne.

The novel compounds of the present invention are prepared by the processillustrated in the following equation:

i=0 i=0 A ca Mo d.

0 III In the above formulae R, R T, X, and Z have the same meaning as.defined hereinbefore; and Z represents a double bond or a saturatedlinkage between C-6 and C-7.

The starting compound of the present invention (1) which is a2,l9-cyclo-allopregnane-3,20-dione derivative, is prepared from thecorresponding 19 -hyd'roxy-A pregnene-3,20-dione, in accordance with mycopending US. patent application Serial No. 231,828, filed of even date,now US. Patent No. 3,158,604, by conventional hydrogenation of the A-double bond, conventional tosylation of l9-hydroxy group of theresulting 19-hydroxyallopregnane-3,2'0-dione, and treatment of the thusobtained 19-tosyloxy-allopregnane-3,20-dione with a strong base, suchasv an alkali metal hydroxide in a polar organic solvent, such as alower hydrocarbon alcohol..

ao-orn rv0-or-n tm In practicing the process outlined above, thestarting.

compoundv (I) is treated with a strong base such as an alkali metalhydroxide, or a strong acid, such as sulfuric, acid, in a suitablesolvent, preferably a polar organic solvent, such as a lower hydrocarbonalcohol, at steam bath temperature for a period of time of the order of4-5 hours thus aifording the coresponding l0a-allopregnan-l'9-ol-3,ZO-dione (II). The latter dione is treated with approximately two moleequivalents of bromine in the presence of hydrogen bromide, preferablyin acetic acid solution, for 5 hours at room temperature, thus affordingthe corresponding 2,4-dibromo derivative, which upon treatment withsodium iodide in methyl-ethyl ketone at reflux temperature for a periodof time of the order of 14 hours, fol lowed by reaction of the producedcompound with chromous chloride in acetone solution by conventionalprocedure yields the corresponding A -lOrx-pregnen-1 9 ol-3,20- dionederivative (II-I). The last named 3,20-dione, upon reaction withethylene glycol in the presence of p-toluenesulfonic acid, yields thecorresponding 3,20-bis-cycloethylenedioxy-A -l0wpregnen-l9-olderivative,which is treated with an organic peracid,,such as monoperphthalic acid,in an inert solvent, preferably chloroform to. produce the corresponding3,ZO-bis-cycloethylenedioxy-5a,6x oxidol0or-pregnan-l9-ol.

Upon reaction of the latter 3,ZO-bis-cycloethylcnedioxy- 5a,6a-oxidocompound with methyl magnesium bromide in an inert solvent, such asether or tetrahydrofuran, followed by conventional working up and thetreatment of the residue with a mineral acid, such as 8% sulfuric acid,and thereafter with thionyl chloride pyridine at about 10 C., forapproximately 4 minutes, there is obtained the corresponding6fi-methyl-A -lu-pregnen-l9-ol 3,20- dione (IV: Z=Z saturated linkage;X=fi-methyl). The latter 6B-methyl derivative is treated with an alkalimetal hydroxide such as sodium hydroxide in a suitable solvent such asmethanol, thus affording the corresponding 60'. methyl derivative (IV:Z=Z =saturated linkage; X= Ot-IBGIhYl) The A-1Oa-pregnen-l90l-3,20-dione derivatives (III) are treated with ethylorthoformate in the presence of ptoluenesulfonic acid, in an inertsolvent, thus affording the corresponding 3-ethoxy-A-10a-pregnadien-19-ol-20- one derivatives, which upon reaction withapproximately 1 molar equivalent N-chlorosuccinimide or another N-chloroamide or imide, in the presence of sodium acetate or acetic acid,yielded the corresponding 6B-chloro-A -10apregnen-l9-ol-3,20 dionederivative (IV: Z=Z =saturated linkage; X=18-chlorine). The aforesaid3-ethoxy- A 5-10a-pregnadien-19-01 2 one derivatives are treated Withperchloryl fluoride in dimethylformamide to produce the corresponding6,8-fluoro-A -l0ot-pregnen-l9-ol 3,20- dione derivatives (IV: Z=Z=saturated linkage; X=,8- fluorine).

Upon treatment of the 6fi-halo-A -3-keto compounds of the presentinvention in an acid medium such as hydrogen chloride-acetic acid, thereare obtained the corresponding 6u-halo derivatives (IV: Z=Z =saturatcdlinkage; X=ahalogen).

The A -1Oa-pr'egnen-l9-ol-3,20-dione derivatives (IV: Z=Z =saturatedlinkage) are treated with 2,3-dichloro- 5,6-dicyano-l,4-benzoquinone ina suitable solvent, such as dioxane, preferably at reflux temperaturefor a period of time of the order of hours to produce the correspondingA -derivatives (IV: Z=double bond; Z =saturated linkage).

The A -10a-pregnen-19-ol-3,2O-dione derivatives (IV: Z=Z :saturatedlinkage) are treated with ethyl orthoformate in the presence ofp-toluenesulfonic acid in an inert solvent, thus affording thecorresponding 3ethoxy- A -10ot-pregnadien-19-ol-20 one, which uponreaction with approximately 1 molar equivalent of 2,3-dichloro-.5,6-dicyano-l,4-benzoquinone, in an inert solvent, preferablytetrahydrofuran, at 0 C. for a period of time of the order of 30minutes, yielded the corresponding M' -10mpregnadien-l9ol-3,20-dionederivatives (IV: Z=saturated linkage; Z =double bond).

When treating the latter [A -compounds with2,3-dichloro-5,6-dicyauo-1,4-benzoquinone in dioxane, at refluxtemperature, for a period of time of the order of 10 hours, there areobtained the corresponding A -pregnatriene derivatives (IV: Z=Z =doublebond).

The compounds of the present invention having a primary hydroxyl group,for example in C19, are conventionally acylated in pyridine with asuitable acylating agent, such as a chloride or an anhydride of ahydrocarbon carboxylic acid of the type defined hereinbefore, thusaffording the corresponding acylates.

The compounds of the present having in the molecule a tertiary hydroxylgroup, e.g. at Cl7, are conventionally esterified in the presence ofp-toluenesulfonic acid with an acylating agent, such as aceticanhydride, caproic anhydride, cyclopentylpropionic anhydride or enanthicanhydride, to produce the corresponding esters.

The compounds of the present invention having a 16cc, Hot-ketonidegrouping, yield the corresponding 1605,17adiols by conventionaltreatment with an acid, such as acetic acid- The obtained diols, uponconventional esterification in pyridine with an acylating agent, as forexample acetic anhydride or caproic anhydride, afford the corresponding16-acylates.

The latter l6a,l7a-diols upon conventional condensation with a ketone oraldehyde, such as benzaldehyde, acetophenone, methyl-ethyl ketone,acetone, and the like, in the presence of an acid, yield thecorresponding 16a, 17a-methylenedioxy derivatives, wherein thesubstituents in the methyle'nedioxy group may be diiferent from those ofthe previously hydrolyzed ketonide grouping.

The following specific examples serve to illustrate the presentinvention, but are not intended to limit the scope thereof Example I Asolution of 10 g. of 16a,17a-isopropylidenedioxy-2,l9-cyclo-allopregnane-3,ZO-dione (obtained in accordance with mypatent application Ser. No. 231,828, filed of even date) in 500 cc. ofethanol was treated with 500 cc. of a 60% aqueous sodium hydroxidesolution and kept for 4 hours at steam bath temperature. The mixture wasthereafter poured into water and extracted with methylene chloride. Theorganic extract was washed abundantly with water,:dried over anhydroussodium sulfate and evaporated to dryness. The residue waschromatographed on alumina, thus alfording 16a,l7oc-iSOpl'Opylidenedioxy-10ct-allopregr1an-19-ol-3,20 dione (Compound No. 1).

Example II A solution of 10 g. of 2,l9cycloallopregnane-3,20-dione(obtained according to my patent application Ser. No. 231,828, filed ofeven date) in 500 cc. of ethanol was treated with 500 cc. of 70%sulfuric acid and kept for 5 hours on the steam bath. It was then pouredinto water and extracted with methylene chloride. The extract wassuccessively washed with water, sodium bicarbonate solution and water.Thereafter it was dried over sodium sulfate and evaporated to dryness.The residue was chromatographed on alumina, thus afiording 10o:-allopregnan-l9-ol-3,ZO-dione (Compound No. 2).

- The starting compounds listed under I (obtained in accordance with theaforesaid patent application) were treated by the same procedure, thusgiving respectively the products set forth under II.

A solution of 2.1 mol equivalents of bromine in 15 cc. of glacial aceticacid was added dropwise to a solution of 1 g. of16oc,17zx-isopropylidenedioxy-10or-allopregnan-19- ol-3,20-dione(Compound No. 1). in 25 cc. of acetic acid containing a few drops of 4 Nhydrogen bromide in acetic acid. After five hours at room temperature,the mixture was poured into ice water and the precipitated dibromoderivative was collected, washed wellwith water, and dried. The driedmaterial was refluxed for 14 hours with 2 g. of sodium iodide in 40 cc.of ethyl methyl ketone and then kept at room temperature for anadditional 12 hours. After dilutionwith water, the product was extractedwith other, washed with sodium thiosulfate solution and water, and theether was removed under reduced pressure.

The crude residue dissolved in 35 cc. of acetone, was treated in anatmosphere of carbon dioxide with a solution of chromous chlorideprepared from 11 g. of chromic chloride. After 20 minutes at roomtemperature, water was added, the mixture was extracted with ether,washed with water until neutral, dried and evaporated. The resultingsubstance was saponified by refluxing for 30 minutes with 0.8 g. ofpotassium carbonate. in 35cc. of methanol and 7 cc. of water and afterextraction with chloroform, it was chromatographed on 50 cc. of ethylacetate- Washed alumina. Recrystallization of the solid fractionsafforded 16a,17a-isopropylidenedioxy-A -a-pregnen-19- ol.-3,20-dion e(Cpd. No. 7).

The Compounds Nos. 2 to 6 inclusive, were treated in accordance with theabove, procedure, thus affording re spectively:

Cpd, No.-

i '8. A IOa pregnen-l9-ol-3,ZQ-dione.

9. 16a-methyl-A -IOaregnen-l9-ol-3,20-di0ne. 10. l'6fi-methyl-A-10opregnen-19-ol-3,20-dione. l'l. A-l'0a-pregnenel7-a,l9-diol-3,20-dione. 12. 16a-methyl-A-l0a-pregnene-l7a,l9 diol 3,20-

dione.

Example I V A suspension of l g. of 16a,17arisopropylidenedioxy-A4110ot-pregnen-l9-olr3,ZO-dione (Cpd., No. 7) in 7.5 cc. of anhydrousperoxide-free dioxane was treated with 1.2 cc, of freshly distilledethyl orthoformate and 0.8 g. of p-toluenesulfonic acid. The mixture wasstirred at room temperaturefor minutes and the resulting solution letstand for 30-rninutes further. 0.8 cc. of pyridine were added and thenwater. The formed precipitate was collected by filtration, water washedand air dried. Recrystallization from acetone-hexane, afforded3-ethoxy-l6a,17uisopropylidenedioxy-A -IOa-pregnadien 19 ol -one (Cpd-.No. 13).,

Following the same procedure, the Compounds Nos. 8 to 12, inclusive,were respectively converted into:

Cpd. No.-

14. 3-ethoxy-A -l0a-pregnadien-19-01-20-one. 15. 3-ethoxy 160a methyl-4-10a-pregnadien-19- ol-20-one. 16. 3-ethoxy 16B methyl-A-10m-pregnadien-19- ol-20-one. 17. i3-ethoxy-A -10oc pregnadiene1;7u,l9-diol--20- one.

18. 3-ethoxy 16a methyl A?-. -10a-pregnadiene 17a,19-diol:20.-one.

Example V A mixture of 5 g of 3.-ethoxy-16a,17u-isopropyl idenedioxy-A-IOaregnadien-19-ol-20-one (Cpd. N0. 13), 2 g. of anhydrous sodiumacetate and- 100 cc. of acetone was treated with 32 cc. of water and thesolution was cooled to a temperature between 0 and 5 C. There was thenadded 1.1 molar equivalents of N-chloro-succinimide and 2 cc. ofglacial-acetic acid and the mixture was stirred between- 0 and 5 C. forminutes. It

was then diluted with water, kept-overnight at 0C. and

the precipitate formed was collected, washed with water, dried undervacuum and recrystallized-from acetone-thus giving 6fi-ChlOI'O-16cz,17ocisopropylidenedioxy-A -10apregnen-l9-ol-3,20-dione (Cpd. No. 19).

Following the same procedure there were treated the Compounds. Nos. 14to 18, inclusive thus affording respectively:

Cpd. No.--

20: 6/8-chloro-A -10a-pregnenelO-ol-3,20 dione.

21. 16a-methyl 6B-chloro-A -10a-pregnen l9-ol-.

3,20-dione.

22 l6p-methyl 6fi-chloro-A 1 0a-pregnenel9-ol- 3,20 -dione.

23. 6,8 chloro A -10a preg nene 170:,19-di0l- 3,20.-dione.

24. 16a-methyl-6B-chloro A -l0u-pregnene-l7a,l9-

diol-3,20-dione.

5 Example VI 1 g. of 3eethoxy-16a,17a-isopropylidenedioxy-A-10apregnadien-l9 0l-20-one (Cpd. No. 13) was dissolved in 25 cc. ofdimethylformamide. The solution was cooled to 0 C. and a stream ofperchloryl fluoride Was passed for 5 minutes; the solution was allowedto come slowly to 20 C.; it was then poured into water and extractedwith ethyl acetate. The extract was Washed with saturated aqueoussolution of sodium bicarbonate, then with water to neutrality, driedover anhydrous sodium sulfate, and evaporated to dryness. Bychromatography over washed alumina there was isolated6fl-fluora-16a,17a-isopropylidenedioxy-A -IOa-pregnen-1'9-ol-3,20-dione(Cpd. N0. 25).

The Compounds Nos. 14 to 18, inclusive, were treated by the aboveprocedure, thus affording respectively:

3,2 0-dione.

28. lop-methyl 6B fluoro A -l0a pregnen-l9-0l- 3,20-dione.

29. 6 6 fiuoro 11 -10 pregnene 17a,19-di0l- 3,20-dione.

Example VII Into a solution of 3 g. of compound No. 19 in cc. of glacialacetic acid was passed a slow stream of dry hydrochloric acid for 4hours, while maintaining the temperature around 15 C. The mixture wasthen poured into ice-water, the precipitate collected, Washed withwater, dried and recrystallized from acetone-hexane to give6a-chloro-16a,17a-isopropylidenedioxy-M-10apregnen-19-ol-3,20-dione(Cpd. No. 31).

Following the same procedure, the Compounds Nos. 20 to 30, inclusive,were respectively converted into;

Cpd. No.

32. 6u+chl0roHM-l01w-pregnen- 19-ol-3,20-dione. 33.l6a-methyl-6a-chloro-A -lOa-pregnen l9 .ol-

3,20-dione,

34. 16B-methyl 6oc-Cl1l0t0 A -10a-pregnen-19-ol- 3,20-dione.

35. 6a-Chl010 M-lOoc-Pregnene 1-7o;,1-9-di 0l-3,20-

dione.

36. l6a-methyl-6a-chloro A -10a-pregnene-17u,19-

diol-3,20-dione.

37. 6a-fluoro-l6a,l7a isopropylidenedioxy- 400cpregnen-l9-ol-3,20-dione.

3,20-dione.

40. 16B-methyl 6a-fluoro-A 10a-pregnen-19-ol- 3,20-dione.

41. 6a-fluoro-A IOa-pregnene 17a,19dl0l-3,20-

dione.

42. 16a-methyl-6a fiuoro-A -l0a pregnen-17a,l9-

diol-'3,20'-dione.

Example Vlll A. mixture of 5 g. of 16a,17a-isopropylidenedioxy- A-l0a-pregnen-19-ol-3,20-dione (Cpd. No. 7). 150 cc. of anhydrousbenzene, 60 cc. of ethyleneglycol distilled over sodium hydroxide and-800 mg. of petoluenesulfonic acid monohydrate was refluxed for 12 hourswith. the use of an adapter for the continuous removal of the waterformed during the reaction. Aqueous sodium bicarbonate solution wasadded to the cooled mixture and the organic phase was separated, washedwith water, dried over anhydrous sodium sulfate and evaporated todryness. The residue crystallized from acetone-hexane to give3,20-bis-cycloethylcnedioxy-l6u,17a-isopropylidenedioxy-A-l0u-pregnen-19-ol (Cpd. No. 43).

A solution of the latter compound in 100 cc. of

chloroform was cooled to C. and mixed with 1.1 molar equivalents ofmonoperphthalic acid in ether solution. The mixture was kept at roomtemperature for 20 hours, diluted with Water, the organic layer Wasseparated, washed with aqueous sodium bicarbonate solution and then withwater to neutral, dried over anhydrous sodium sulfate and evaporated todryness. Crystallization from acetone-hexane gave3,20-bis-cycloethylenedioxy-a,6a-oxid-o-16a,17aisopropylidenedioxy-apregnan-l9-ol (Cpd. N0. 44).

To a solution of 40 cc. of 4 N methylmagnesium bromide in ether wasadded, with stirring, a solution of 2 g. of the latter 50,6a-OXid6 in 60cc. of dry tetrahydrofuran and the stirred mixture heated under refluxfor 30 minutes. The condenser was then replaced by a calciumchloridetube, the ether allowed to boil off and when the internal temperaturereached 54 C., the condenser was readapted and the mixture refluxed foran additional 4 hours. 400 cc. of a saturated solution of ammoniumchloride was added slowly to the cooled mixture which was then stirredfor minutes before transfer to a separatory funnel. Ethylacetate wasadded, the organic layer separated, washed, dried and evaporated,whereupon crystallization of the residue from aqueous methanol gave3,20-bis-cyc1oethylenedioxy-6p3-methyl- 160:,1704isopropylidenedioxy-10a pregnane-5m,l9-diol (Cpd. No. 45).

A solution of 2.0 g. of compound No. 45 in 70 cc. of methanol and 7 ml.of 8% aqueous sulfuric acid was refluxed for 40 minutes. It was thenneutralized with saturated sodium carbonate solution, concentrated toca. ml. in vacuo and poured into water. The formed precipitate wasfiltered off and washed thoroughly with water. Recrystallization fromacetone gave 6fl-methy1- 16oz,17a-isopropylidenedioxy-lOa-pregnane 5a,l9diol- 3,20-dione (Cpd. No. 46).

A solution of 1 g. of the latter compound in 7 cc. of dry pyridine wascooled to 10 C., treated with 0.4 cc. of thionyl chloride and themixture was allowed to stand for 4 minutes at this temperature. Icewater was added and the crystalline precipitate was filtered, washed anddried, yielding 6B-methyl-16a,Hot-isopropylidenedioxy- A-10a-pregnen-l9-ol-3,20-dione (Cpd. No. 47).

' When applying the above sequence of reactions to Compounds Nos. 8 to12, inclusive, there were respectively obtained as final products:

Cpd. No.

48. 6,B-methyl-A -l0a-pregnen-19-ol-3,30-dione.

49. 6p,16a-dimethyl-A -10opregnen-l9 o1 3,20-

dione.

50. 6,8,16B-dimethyl-A -1Oar-pregnen-19 01 3,20-

dione.

51. 6B-methyl-A -lOu-pregnene-170:,19 diol 3,20-

dione.

52. 6,8,16a-dimethyl-A -lOa-pregnene-17u,19 diol- 3,20-dione.

Example IX 1 g. of Compound No. 47 was dissolved in 20 cc. of methanolcontaining 0.2 g. of sodium hydroxide and the mixture was kept for oneand a half hours at room temperature, then poured into water andextracted with methylene chloride. Evaporation of the methylene chloridesolution and crystallization of the residue from acetonehexane yielded6a-rnethyl-16u,l7oa-isopropylidenedioxy-A -1Oaregnen-19-ol-3,20-dione,(Cpd. No. 53).

The Compounds Nos. 48 to 52, inclusive, were treated by the aboveprocedure, atfording respectively:

Cpd. No.--

54. 6u-methyl-A -IOa-pregnen-I9-o1-3,20-dione. 55. 6a,l6a-dimethyl-A-lO-pregnen l9 o1 3,20-

dione.

56. 6a,l6fl-dimethyl-A -IOaregnen 19 ol 3,20-

dione. 57. 6u-methyl-A -IOa-pregnene-17a-pregnene 17a,

19-diol-3,20-dione. 58. 6a,16a-dirnethyl-A -10oc-pregnene17a,19 diol-3,20-dione.

Example X A mixture of 500 mg. of Compound No. 7, 10 cc. of dioxane and350 mg. of 2,3-dichloro-5,6-dicyano-1,4- benzoquinone was refluxed for10 hours. cooled, the 2,3-dichloro-5,6-dicyano 1,4 benzohydroquinoneformed during the reaction filtered off, and the filtrate evaporated todryness. The residue was dissolved in acetone and filtered through 10 g.of alumina. Crystallization from acetone-hexane-gave16a,l7a-isopropylidenedioxy-A -l0a-pregnadien-19-ol-3,20 dione (Cpd.No.59).

The Compounds Nos. 8 to 12 inclusive, were treated by the aboveprocedure, to produce respectively:

Cpd. No.

60. A -lOar-pregnadien-l9-o1-3,20-dione.

61. ,l6a-methyl-A l0a-pregnadien 19 o1 3,20-

dione.

62. 16fl-methyl-A -IOaregnadien 19 o1 3,20-

dione.

63. A -IOa-pregnadiene-lh,19-diol-3,20-dione.

64. 16a-methyl-A -IOa-pregnadiene 170;,19 diol- 3,20-dione.

Example XI The Compounds Nos. 19, 25, 31,37, 47 and 53 were treatedfollowing the procedure described in Example X, thus affordingrespectively:

Cpd. No.,-

65. 6;8-ch1or0-16a,17o isopropylidenedioxy AIOa-pregnadien-19-ol-3,20-dio'ne.

66. 6fl-fluoro-l6a,17a isopropylidenedioxy A10a-pregnadien-l9-ol-3,20-dione. 67. 6a-chloro-l6a,17 xisopropylidenedioxy A 10aregnadicn-l9-ol-3,20-dione. 68.6oc-flIlOIO-16cc,17oc isopropylidenedioxy AlOu-pregnadien-19-ol-3,20-dione.

69. 6fi-methyl-16u,17a isopropylidenedioxy A10a-pregnadien-l9-ol-3,20-dione.- 70. 6OL-I1'16thYl-16a,1706isopropylidenedioxy A 1 Omreguadien-19-ol-3,20-dione.

Example XII A solution of 1 g. of 3-ethOXy-'16OL,17OL-lSOPIOPY1ldfiIlB-dioxy-A -lOu-prcgnadien-19-ol-20-one (Cpd. No. 13) in 20 cc. oftetrahydrofuran was cooled to 0 C. and there were added 1.05 molarequivalents of 2,3-dich1oro- 5,6-dicyano-1,4-benz0quinone and mg. ofp-toluenesulfonic acid. The resulting mixture was further stirred at 0C.for 30 minutes. The. precipitated hydroquinone was filtered off and 100cc. of methylene chloride were added to the filtrate.

The organic solution was washed with 5% aqueous sodium hydroxidesolution until the washings were colorless, then with water toneutrality, dried over anhydrous sodium sulfate and evaporated todryness. Crystallization from acetone-hexane gave16a.Hot-isopropylidenedioxy A -10a-pregnadien-l9-ol-3,20-dione (Cpd. No.71).

The compounds Nos. 14 to 18, inclusive, were treated in accordance withthe above procedure, thus furnishing.

Cpd. No.-

72. A -10a-pregnadien-19-ol-3,20-d.ione.

73. 16a-methyl-A '5-lOa-pregnadien-l9-ol-3,20-dione.

74. l6fi-methyl-A -lOareguadien-19-ol-3,20-dione.

75. A -IOa-pregnadiene-I7a,19-diol-3,20-di0ne.

76. 16a-methyl-A -IOuregnadiene 17u,19 diol- 3,20-dione.

It was then and a few drops of 3 N perchloric acid and stirred at :roomtemperature for 2 hours. After diluting with water the chloroform layerwas separated, Washed with aqueous rsaturated sodium bicarbonatesolution and then with Water, the chloroform was distilled and theresidue was purified by chromatography on neutral alumina, thus yieldingl6oc,-17a (ethylidenedioxy) 6a-chloro-A -10upregnen-19-ol-3,20-dione(Cpd. No. 115).

Example XXII To a solution of 5 g. of a-allopregnane-17a,19-diol-3,20-dione (Compound No. 5) in 100 cc. anhydrous benzene there wereadded 1 g. of p-toluenesulfonic acid and 10 cc. of caproic anhydride andthe mixture was allowed to stand for 24 hours at room temperature,poured into ice and water, and the resulting mixture stirred to effecthydrolysis of the excess anhydride. The benzene layer was separated andwashed 'with 10% sodium carbonate solution and water. Drying evaporationand crystallization of the residuefrom ether-hexane produced10a-a1lopregnane-l7a,19-diol-3,20-dione dica'proate (Cpd. No.1'16).

When applying the same procedure to Compounds Nos. 11, 12, 35, 41, 57,63, 75, 85, 92, 103 and 113, there were respectively obtained:

117. 11 -100: pregnene-17a,l9-diol-3,20-dione dicapr-oa'te.

118. 16a methyl-A 4Oa-pregnene-17a,19-dio1-3,20-

dione dicaproate.

119. 6a chloro A -10a-regnene-l7u,1-9-diol-3,2O-

dione di-caproate.

120. 60a fluoro A -10oc-pregnene-l7a,19-dio1-3,20-

dione dicaproate.

121. 60c methyl A -10oc-pregnene-17oc,19-diol-3,20-

dione dicaproate.

122. A -10a-pregnadiene-17a,19-diol-3,20-dione dicaproate.

123. A IOa-pregnadiene-17a,l9-diol-3,20-dione dicaproate.

124. A 10m-pregnatriene-17u,l9-diol-3,20-dione dicaproate.

125. A -lOa-pregnene-17a,19-di01-3,20-dione 17-caproate-19-acetate.

126. A 10a pregnene-16a,17a,19-triol-3,20-dione trica'proate.

'127. A 10a pregnene-16a,17u,19-triol-3,20-dione 16,19-diacetate17-caproate.

Example XXIII A suspension of 1 g. of Compound No. 117 in 60 cc. ofmethanol was treated with a solution of 1 g. of potas sium carbonate in6 cc. of water; the mixture was boiled under reflux for 1 hour and thencooled in ice and diluted 'with water. The formed precipitate wascollected and recrystallized from acetone-hexane to yield A -10r-pregnene-17a,19-diol-3,20-dione 17-ca'proate (Cpd. No. 128').

I claim:

1. A compound of the following formula:

CH3 18/0 I H Z :1 j

wherein X is selected from the group consisting of hydrogen, u-fluorine,,B-fiuorine, ot-chlorine, B-chlorine', ot-methyl and ,B-methyl; R isselected from the group consisting of from the group consisting ofhydrogen, w-hydr'oxyl, a

hydrocarbon ca'rboxylic acyloxy of less than 12 carbon atoms, a-methyland ,B-methyl, with T being other than hydrogen when R equals hydrogen;T and R together form the group wherein R and R are selected from thegroup consisting of hydrogen and a hydrocarbon residue of up to 8 carbonatoms; R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; and Z isa member of the group consisting of a double bond and a saturatedlinkage between C-l and C-2.

2. 16u,17u isopropylidenedioxy A 10oz pregnen- 19-ol-3,20-dione.

. 16a-methyl-A -10a-pregnen-19-ol-3,20-dione. 16,6-methyl-A-l0oz-pregnene-l9-ol-3,20-dione.

A -l0a-pregnene-17ot,19-dio1-3,20-dione. 16oz-methyl-A-IOaregnene-l7ot,l9 diol-3,2O-dione. 6,8-chloro-A-10u-pregnen-l9-ol-3,20-dione. 6ot-fluoro-A-1Ou-pregnen-19-01-3,20-dione. 6ot-methyl-A-1Oa-pregnen-19-ol-3,20-dione.

10. A -1Oaregnadien-19-ol-3,20-dione.

11. 16a methyl A 10a pregnadien 19 ol 3,20- dione.

12. 60c chloro 1604,170: isopropylidenedioxy Aloa-pregnadien19-ol-3,20-dione.

13. 6oz chloro 16oc,17cc isopropylidenedioxy Al0a-pregnen-l9-ol-3,20-dione.

14. 6a fluoro ;,170; isopropylidenedioxy A 10a-pregnen-19-ol-3,20-dione.

15. 60a methyl 16,17m isopropylidenedioxy Al0a-pregnen-19-ol-3,20-dione.

16. 6a,l6ot-dimethyl-A -l0ot-pregnen-19-0l-3,20-dione.

17. A compound of the following formula:

@252 if; I 5Q wherein X is selected from the group consisting ofhydrogen, fluorine, chlorine and methyl; R is selected from the groupconsisting of hydrogen, a hydroxyl group and a hydrocarbon carboxylicacyloxy group of less than 12 carbon atoms; T is selected from the groupconsisting of hydrogen, ot-hydroxyl, u-hydrocarbon carboxylic acyloxy ofless than 12 carbon atoms, tat-methyl and fi-methyl; T and R togetherform the group (References on following page) Example XIII A suspensionof 1 g. of 6-chloro-16a,l7a-isopropylideriedioxy-M-lOa-Pregnen-19-0l-3,20-di0ne(Cpd. 31) in 7.5 cc. of anhydrous peroxide-free dioxa ne was treatedwith 1.2 cc. of freshly distilledjethyl orthoformate. and 0.8 g. ofp-toluenesulfonic acid. The mixture was stirred at room temperature for15 minutes and the resulting solution let stand for 30 minutesfurther.0.8 cc. of pyridine were added and then water. The formed precipitatewas collected by filtration, water washed and air dried.Recrystallization from acetone-hexane afforded 3-ethoxy-.6-chloro-l6a,17a-isopropy1idenedioxy-A IOa-pregnadien- 19-ol-20-one (Cpd.No. 77). l

The latter compound was treated in accordance with Example XII, thusyielding 6-c'hloro-1. 6a,17a-isopropylidenedioxy-A -IOa-Pregnadien -19ol-3',20-dione (Cpd. No. 78).

The Compounds Nos. 37 and 53, were treated by the same procedures, thusaifording, respectively, as final products:

6-fiuoro 16a,17 x isopropylidenedioxy- Azfi-lOa-pregnadien-l9-ol-3,20-dione (Cpd. No. 79) and fi-methyl-16a,l7a-isopropylidenedioxy-A -10a ,pregnadien 19-01- 3,20-dione (Cpd.N0. 80).

Example XIV The compounds Nos. 71 to 76, inclusive were treated inaccordance with Example X, thus furnishing respective- Example XV Amixture of 1 g. of 10 -allopregnan-19-01-3,20-dione (Cpd. No. 2), 4 cc.of pyridine and 2 cc. of acetic anhydride was kept at room temperatureovernight, poured into ice Water, the formed precipitate was filtered,washed with water and dried. Crystallization from acetonehexane gave10a-allopregnan-19-ol 3,20-dione acetate (Cpd. No. 87).

Following the same procedure, there were treated the Compounds Nos. 7 to12 inclusive, thus furnishing respectively:

Cpd. No.-

8 8. 16 a, 17 a-isopropylidenedioxy-A l Oa-pregnen- 19-ol-3,20-dioneacetate. 1

89. A -1Oa-preguen-l9-ol-3,20-dione acetate.

90. 16a-methyl A -IOwpregnen 19-ol-3,20-di0ne acetate.

91. 16,6-methyl-A -10a-pregnen-19-ol-3 ,20-dione acetate.

92. A -10a-pregnene-17a,19-diol-3,20-dione 19- acetate.

93. 16a-methy1-A -10a-pregnene-17qe19-di l-3,20-

Example XVI The compounds Nos. 20, 38, 54, 60, 61, 67, 72 and 82 weretreated according to Example XVthus aifofrdirl g respectively:

Cpd. No.-

94. 6,6-chloro-A -1Oa-pIegnen-19-ol-3,20-dione acetate.

95. 6a -fluor.o-A -10a-pregnen-19-ol-3,20rdione acetate.

9 6. 6a-methyl-A 10a-pregnen-1 9-ol-3,20,-dione dione.

97. A -1O -pregnadien-19rol-3,20-dione acetate.

98. lfia methyl-A -l0a pregnadien 19-o13,20-

dione acetate.

99. 6a-Chl0l'O-1 6a, 17a-isopropy1idenedioxy-A10a-pregnadien-19-3,20-dione acetate.

100. Att emwpregnadien 1.9-ol-3;20-dioneacetate.

101. A 4 -1Qa-pregnatrien-19-ol-3,20-dione acetate.

Example XVII The starting compounds of Examples XV and XVI were treatedaccording to Example XV, except=that acetic anhydride was substituted bycaproic anhydride, enanthic anhydride and undecenoic anhydride thusaffording respectively the corresponding caproates, enanthates, andundecenoates.

Example XVIII 1 g. of 16a, 17a-isopropylidenedioxy-10a-allopregnan-19-ol-3,20-dione (Cpd. No. l) was heated on the steam bath with .100 cc.of acetic acid under nitrogen for 7 hours, it was then concentratedunder vacuumto a small volume and poured into water. The precipitate wascollected,washed well with water, dried and recrystallized fromacetone-hexane, thus furnishing IOa-Eillopregnane-.l6 a,17a,19-triol-3,20-dione '(Cpd. 102).

The Compounds Nos. 7, 31, 37, 53, 59, 67,68, 71, 78, and .81 weretreated by the same procedure, thus furnishing respectively:

103. A IOa-pregnene-l6a,17oz,19-triol-3,20-dione.

104. 6a chloro-M-lM-pregnene-16a,-17a,19-triol-3,

ZO-dione.

105. 6a fluoro-A -10a-pregnene-16a,17a,19-triol-3,

20-dione.

106. 6a methyl-A -10a-pregnene-16a,17a,19-trio1-3,

20-dione.

107. A 4 10a pregnadien 16a,17oc,19-t1l013,20

dione.

108. 6a chloro-A 10a-pregnadien-16a,17a,19-triol -3,20-dione.

109. 6.0: fluoro-AM-10a-pregnadien-16a,17a,l9-triol3,20-dione.

110. A 10a pregnadien-l6a,17a,19-triol-3,20-

dione.. 111. 6 ch1oro-A -1.0 -pregnadien-16a,17a,19-triol- 3,20-dione. l112 A 10a pregnatrien-l6a,l7a,19-triol-3,20- one.

Example XIX The Compound No. 103 was treated in accordance with ExampleXV, thus giving A -l0a-pregnene-16a,l7a,19- triol-3, 20-dione16,19-diaceta-te (Cpd. No. 113.).

When applying the same procedure to the rest of the final compounds setforth in Example XVIII, there were obtained the corresponding16,19-diacetates.

Example XX Example XXI A solution of 500 mg. of compound No. 104 in 20cc. of chloroform Was treated with 1 g. of acetaldehyde 13 14 ReferencesCited by the Examiner Fieser et al.: Steroids, pages 138-142 (1959 ed.),

Reinhold Pub. Company, New York. UNITED STATES PATENTS Mayor et 211.: J.Chem. Soc., pages 2792-2800 (1960). 3,013,025 12/61 Zaffarom 26O'397-1Mayor st 211.: J. Chem. Soc. pages 2800-2802 (1960).

OTHER REFERENCES 5 Rappoldt et a1.: Rec. Trav. Chem. 80, pages 43-46,

J c 1961. Castells G1 8.1.! J. Chem. 500., pages 2627-2639 (1960).

Chen.: Tetrahedron 3, pages 43-48 (1958). LEWIS GOTTS, Primary Ex miner.

1. A COMPOUND OF THE FOLLOWING FORMULA: 